MOOD STABILIZERS TARGET THE BRAIN ARACHIDONIC ACID CASCADE Administration to rats at therapeutically relevant doses of each of the FDA-approved mood stabilizers -- lithium, valproate, carbamazepine, and lamotrigine -- downregulated brain arachidonic acid (AA) metabolic markers but not docosahexaenoic acid markers. The first three agents, which are preferred for treating bipolar mania, decreased turnover of AA in brain phospholipids, expression of cyclooxygenase (COX)-2 and AA-selective cytosolic phospholipase A2 or acyl-CoA synthetase, and the concentration of prostaglandin E2. Lamotrigine, preferred for bipolar depression, downregulated COX-2 transcription and activity. These studies lend further support to our hypothesis that the brain AA cascade is the common target of effective mood stabilizers, and suggest that measuring AA cascade markers in the rat can be used to screen for new, less-toxic, bipolar disorder agents (Refs. 2, 4, 5 and 6). MOOD STABILIZERS UPREGULATE EXPRESSION OF BRAIN NEUROTROPHIC FACTORS Brain derived neurotrophic factor (BDNF) and B-cell lymphoma-2 (Bcl-2) are involved in neuronal signaling, cell survival and plasticity. Decreased brain levels of these factors occur in bipolar disorder. We showed that chronic administration to rats of lithium, valproic acid, carbamazepine, or lamotrigine, to produce therapeutically relevant plasma concentrations, increased BDNF and Bcl-2 levels in the cytosolic fraction of the frontal cortex. This common effect of the mood stabilizers on brain neuroprotective factors may be mediated by downregulation of AA metabolism (Reference 1). ANTIDEPRESSANTS THAT INCREASE SWITCHING OF BIPOLAR DEPRESSION TO MANIA UPREGULATE RAT BRAIN ARACHIDONIC ACID CASCADE. The antidepressants, fluoxetine and imipramine, when given to bipolar depressed patients increase the tendency to switch to mania, whereas the antidepressant bupropion does not. We tested the hypothesis that antidepressants that increase switching upregulate the rat brain AA cascade. Consistent with this prediction, chronic fluoxetine and imipramine increased rat brain AA turnover, cytosolic phospholipase A2 mRNA, activity and protein, and AP-2 binding, but bupropion did not. These data suggest that bipolar mania and upregulated brain AA metabolism are functionally associated. They also indicate that our fatty acid method in rats could be used to screen for antidepressants that would not increase switching of bipolar depression to mania (Ref 3).